Do insights from mice imply that combined Th2 and Th17 therapies would benefit select severe asthma patients?

Matthew E. Poynter


Asthma is a multi-faceted syndrome, and understanding the key cellular and molecular participants is an important objective, so that clinicians can deliver targeted care. Most asthmatics can be effectively treated through the use of beta-agonists and corticosteroids. However, there remains a considerable percentage of individuals with an asthma diagnosis for whom these conventional therapeutic approaches are ineffective. These patients are considered to have severe disease (1), and severe asthma disproportionately accounts for the socioeconomic impacts of asthma. It has become an important objective for researchers to identify the contributors to severe asthma and to develop approaches to target these events. While allergic asthma is typically caused by an over-exuberant type-2 response (now appreciated to come from CD4 T helper cells and
type-2 innate lymphoid cells), in which cytokines including IL-4, IL-5, and IL-13 drive IgE class switching, eosinophil development and survival, and mucus production, the asthma community has for some time appreciated the epidemiological connections between severe asthma and neutrophils. Elevated levels of sputum or bronchoalveolar lavage neutrophils correlate with more severe disease. Mechanistic insight into the cause of elevated airspace/airway neutrophils came from the findings that IL-17 (typically IL-17A and IL-17F) derived predominantly from CD4+ T helper cells (Th17 cells; although type-3 innate lymphoid cells and other leukocytes are producers as well) is an important promotor of neutrophil production and influx in severe asthma. Mouse models of disease demonstrated that Th17 cells were sufficient to cause steroid-refractory disease, and other work demonstrated that Th17 cells were in some instances necessary for several pathophysiological manifestations in asthma models (2). However, the mechanistic contribution of IL-17 and even of neutrophils remains both controversial and contentious. Nonetheless, there are disorders in which IL-17 and neutrophils are important contributors to disease, and IL-17—neutralizing approaches have been developed and are being evaluated clinically. Whether neutralization of IL-17 in selected populations of severe asthmatics will be safe and elicit benefit remains to be fully elucidated, and animal models are an important stepping stone to such definitive clinical trials.